Article ID | Journal | Published Year | Pages | File Type |
---|---|---|---|---|
5562243 | Toxicology Letters | 2016 | 34 Pages |
Abstract
6-Propyl-2-thiouracil (PTU)-induced hypothyroidism disrupts neuronal/glial development. This study sought to identify the sensitive immunohistochemical parameters of developmental neurotoxicity (DNT) following PTU-exposure, as well as their responses in a 28-day toxicity study in adults. In the developmental exposure study, pregnant rats were treated with 0, 1, 3, and 10 ppm PTU in drinking water from gestational day 6 to postnatal day (PND) 21 and pups were examined on PNDs 21 and 77. In the adult-stage exposure study, 5-week-old male rats were treated with 0, 0.1 and 10 mg PTU/kg by oral gavage for 28 days. In the developmental exposure study on PND 21, there were fewer GFAP+, PAX6+, and DCX+ cells in the subgranular zone (SGZ) of the hippocampal dentate gyrus at â¥3 or 10 ppm. Regarding synaptic plasticity-related molecules, there were fewer EPHA4+ and ARC+ cells in the dentate granule cell layer. Regarding GABAergic interneuron subpopulations, there were more RELN+, CALB2+, and SST+ cells and fewer PVALB+ cells in the dentate hilus. There were also differences in the numbers of RELN+, PVALB+, CALB2+, and NPY+ cells in the cerebral cortex, and RELN+, PVALB+, and SST+ cells in the cerebellar cortex. Most of these changes were sustained until PND 77. Following adult-stage exposure (10 mg/kg), there were fewer SGZ DCX+ cells, but more RELN+ and SST+ cells in the dentate hilus. Results suggest that GABAergic interneuron populations in cortical tissues, hippocampal neurogenesis, and synaptic plasticity are sensitive to PTU-induced DNT during development. In contrast, only hippocampal neurogenesis was sensitive to adult-stage exposure.
Keywords
FOSTSHPTUDcxGCLFBJ osteosarcoma oncogenecalbindin-D-29KEphA4Pax6retrosplenial agranular cortexSGZCALB2DNTSox2EomesoderminReelinRELNcox2DABPvalbGFAPPNDPCNADpysl3SSTVIPNPYRSA6-propyl-2-thiouracil3,3′-diaminobenzidineTHsProliferating Cell Nuclear Antigenγ-aminobutyric acidGABAergic interneuroncornu ammonisTerminal deoxynucleotidyl transferase dUTP nick end labelingTriiodothyronineTUNELthyroxinePaired box 6EOMESdoublecortingestational daypostnatal daySomatostatinCyclooxygenase-2Developmental neurotoxicityactivity-regulated cytoskeleton-associated proteinArcgranule cell layerToxicity studysubgranular zoneSex determining region Y-box 2RatHippocampal neurogenesisThyroid-stimulating hormoneThyroid hormonesParvalbuminGlial fibrillary acidic proteinvasoactive intestinal peptideHypothyroidismGABANeuropeptide Y
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Authors
Ayako Shiraki, Takeshi Tanaka, Yousuke Watanabe, Fumiyo Saito, Yumi Akahori, Nobuya Imatanaka, Toshinori Yoshida, Makoto Shibutani,